The aims of gastroesophageal reflux disease (GERD) treatment are symptom relief and healing of oesophagitis. Besides proton pump inhibitors (PPIs), prokinetic agents are also commonly prescribed to treat GERD. Domperidone, a well-known antiemetic, is an example of a prokinetic agent. It is a dopaminergic blocker that increases lower oesophagus sphincter pressure and activates gastric motility. We carried out a systematic review and meta-analysis to explore the benefits of domperidone in addition to PPI therapy for GERD. We searched for publications comparing PPI plus domperidone to PPI monotherapy in terms of symptom improvement in GERD (until 21 April 2022) on PubMed, Scopus, Google Scholar, Web of Science, Cochrane Library, WHO’s International Clinical Studies Registry Platform, and ClinicalTrials.gov without restricting date, language, or study design. The protocol was registered in PROSPERO (CRD42021242076). This meta-analysis incorporated 11 studies with a total of 841 participants (419 in the PPI plus domperidone group and 422 in the PPI monotherapy group). The combination of a PPI and domperidone resulted in a significant reduction in global GERD symptoms. Adverse events associated with PPI plus domperidone treatment were similar to those associated with PPI monotherapy. In conclusion, the combination of domperidone and a PPI is generally safe and effective in treating GERD as compared with that of PPI alone.